These results prompted experimental treatment with a poly(ADP-ribose) polymerase (PARP) inhibitor in a patient whose tumor was refractory to irradiation and medical therapy, which led to a prolonged response and enabled the discovery of mutational destabilization of the autoinhibitory PARP1 alpha-helical domain (HD) as an yet unrecognized mechanism underlying acquired PARP inhibitor resistance. The gene discussed is PARP1; the disease is neoplasm.